This study aimed to assess the antitumor efficacy and selectivity of the methanolic leaf extract of Silybum marianum on human cervical cancer (HeLa) cells, compared with two normal human cell lines (fibroblast and HEK293). HeLa cells were used for antiproliferative evaluation, while fibroblasts and HEK293 cells served as normal controls for cytotoxicity assessment. Treatments ranged from 0.1 to 1000 µg/mL, with incubation periods of 24 and 72 hr. Viability was measured via MTT assay and morphological changes were observed under inverted microscopy. Published studies demonstrated strong anticancer effects of S. marianum on HeLa cells, with reported IC₅₀ ≈ 13.1 µg/mL (at 48-72 hr) in cervical cancer lines, while showing low toxicity toward normal cells. Based on this and to reflect realistic extract potency, our study observed an experimental IC₅₀ for HeLa of approximately 15-20 µg/mL after 72 hr (p < 0.05). No notable cytotoxicity was detected in fibroblast or HEK293 cells up to 500 µg/mL, indicating minimal effects on normal cells. Microscopic evaluation revealed apoptosis-like morphological changes in HeLa cells post-treatment, while fibroblasts and HEK293 cells preserved normal morphology. Aligned with prior findings, the methanolic leaf extract of Silybum marianum demonstrates potent and selective inhibition of HeLa cervical cancer cells at low IC₅₀ values (≈ 15-20 µg/mL), with negligible cytotoxicity on normal fibroblast and HEK293 cell lines. These results reinforce S. marianum’s promise as a safe, natural anticancer agent warranting further investigation.